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EP3890888A2 - Dispositif de dosage de liquides pour l'émission ballistique de quantités de dosage dans la plage de nanolitres, procédé de dosage de liquides et pointe de pipette pour celui-ci - Google Patents

Dispositif de dosage de liquides pour l'émission ballistique de quantités de dosage dans la plage de nanolitres, procédé de dosage de liquides et pointe de pipette pour celui-ci

Info

Publication number
EP3890888A2
EP3890888A2 EP19813503.0A EP19813503A EP3890888A2 EP 3890888 A2 EP3890888 A2 EP 3890888A2 EP 19813503 A EP19813503 A EP 19813503A EP 3890888 A2 EP3890888 A2 EP 3890888A2
Authority
EP
European Patent Office
Prior art keywords
deformation
liquid
tip
pipetting
dosing
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19813503.0A
Other languages
German (de)
English (en)
Inventor
Jörg Pochert
Andreas Ernst
Nils Lass
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hamilton Bonaduz AG
Biofluidix GmbH
Original Assignee
Hamilton Bonaduz AG
Biofluidix GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hamilton Bonaduz AG, Biofluidix GmbH filed Critical Hamilton Bonaduz AG
Publication of EP3890888A2 publication Critical patent/EP3890888A2/fr
Pending legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/021—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
    • B01L3/0217—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids of the plunger pump type
    • B01L3/0237—Details of electronic control, e.g. relating to user interface
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/021—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
    • B01L3/0217—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids of the plunger pump type
    • B01L3/0224—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids of the plunger pump type having mechanical means to set stroke length, e.g. movable stops
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/0241—Drop counters; Drop formers
    • B01L3/0268—Drop counters; Drop formers using pulse dispensing or spraying, eg. inkjet type, piezo actuated ejection of droplets from capillaries
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/0275—Interchangeable or disposable dispensing tips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0896—Nanoscaled
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/043—Moving fluids with specific forces or mechanical means specific forces magnetic forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0478—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure pistons
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or chambers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027—General features of the devices
    • G01N2035/1032—Dilution or aliquotting
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027—General features of the devices
    • G01N2035/1034—Transferring microquantities of liquid
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N35/1016—Control of the volume dispensed or introduced

Definitions

  • Liquid dosing device for ballistic delivery of dosing quantities in the nanoliter range, liquid dosing method and pipette tip for this
  • the present invention relates to a liquid dosing device for ballistic delivery of a discrete dosing amount of dosing liquid in a dosing volume range from 0.3 nl to 900 nl from a dosing liquid supply, comprising:
  • a pipette tip receiving device which, at least in a ready-to-dose operating position of the liquid metering device, defines a receiving space which extends along a virtual receiving axis and is designed to receive a section of a pipetting tip
  • a trigger plunger which is movable relative to the pipette tip receiving device and which can be displaced between a standby position which is more withdrawn from the receiving space and a trigger position which projects more strongly into the receiving space
  • a with the release tappet coupled motion-transmitting publishing drive which is designed to shift the release tappet we at least in a jerky manner from the ready position to the release position
  • a control device which is connected to the transmission drive to control the operation of the relocation drive
  • Such a liquid metering device is known from WO 2006/076957 A1.
  • This document discloses to accommodate pipette tips specially designed for this liquid metering device with a tube or tube section at their longitudinal end in a pipette tip receiving device.
  • the longitudinal metering end has a metering opening through which metering liquid is dispensed in a metered manner.
  • hose or tube section By means of short mechanical impulses, which are exerted by the tappet on the specially designed hose or tube section of the pipette tip, discrete dosing liquid quantities in the nl range can be thrown out of the hose or tube section.
  • the hose or pipe section has preferably along a hose or tube axis a cross-section which is essentially constant in size and shape.
  • the metered quantity thrown off by the mechanical impulse transfer covers a distance in free flight as metering drops, which is why this dispensing of the metered quantity is referred to in the present case as "ballistic".
  • the pipetting tip has a coupling formation which is designed for coupling to a pipetting channel of a pipetting device.
  • the latter longitudinal end is therefore referred to below as the "coupling longitudinal end”.
  • the known pipette tip which he stretches along a virtual tip axis, has a reservoir space in which a dosing liquid supply can be accommodated axially with respect to the tip axis between the coupling longitudinal end and the hose or tube section close to the dosing longitudinal end.
  • the known liquid dosing device uses the incompressibility of dosing liquids.
  • a pressure wave induced in the dosing liquid by the mechanical impulse propagates in the dosing liquid in two opposite directions along the tip axis.
  • the metering liquid supply accommodated in the reservoir space rests above the hose or pipe section, which represents a large, inert mass compared to the smaller metering liquid quantity accommodated in the hose or pipe section. Therefore, the mechanical impulse leads to the metering opening as the location the least mechanical and fluid mechanical resistance to detach a discrete dosing amount that leaves the pipette tip in the axial direction.
  • a disadvantage of the known liquid metering device is the need to use specially designed pipetting tips, namely those that have the described hose or tube section with a substantially constant, small cross section between their free metering opening and the reservoir space.
  • the object of the present invention to provide a technical teaching which improves the aforementioned fluid metering device in such a way that it can be operated with commercially available pipetting tips which are not specifically designed for use in the liquid metering device must be designed.
  • the technical teaching provided by the present invention is intended to enable the use of commercially available pipette tips, the metering opening of which is not at a free end of a tube or tube section with a constant and, compared to the other cross sections of the pipette tip, outside the tube or tube portion cut, small cross-sections with a cross-sectional area in the range of 0.075 to 0.75 mm 2 and with a length of more than 2 mm.
  • the commercially available conventional pipetting tip can have a short cylindrical collar at the longitudinal metering end, which is formed between the tapering region between the longitudinal metering end and the coupling longitudinal end and the metering opening.
  • this collar has no length of more than 2 mm and is therefore unsuitable for mechanical impulse transmission.
  • conventional pipette tips preferably taper right up to the metering opening.
  • a liquid metering device of the type mentioned which has a first and a second deformation formation, the first and the second deformation formation between them being an axial longitudinal region of the receiving space extending along the virtual axis
  • the trigger plunger is in its trigger position in the deformation area of the receiving space.
  • the basic idea of the present invention is to deform an axial section of conventional pipette tips, which do not have a section, which is designed for mechanical pulse transmission for the purpose of delivering a discrete metering quantity, by the two deformation formations of the liquid metering device as a deformation section such that the thus deformed section of the pipette tip can be used for dosing dosing volumes in the nano-liter range by mechanical impulse transmission by means of the trigger plunger.
  • an originally arbitrarily shaped and configured pipette tip can be deformed at least in sections by deformation by means of relative approximation of the first and second deformation formation to one another for a predetermined period of time, in which the trigger plunger transmits a mechanical pulse to the deformation section of the pipette tip and since a discrete dosing quantity can be thrown out of the dosing liquid in a manner known per se from the pipette tip through its dosing opening.
  • the liquid metering device of the present invention differs significantly from that of the above-mentioned prior art by the first and the second deformation formation, so that the definition of the liquid metering device does not initially depend on whether a pipette tip is actually received in the pipette tip receiving device or whether the pipette tip receiving device is only designed to receive a pipette tip.
  • the trigger plunger is in its release position in the deformation region of the receiving space causing a recorded pipette tip to ensure that the trigger plunger trigger the dosing quantities to transmit the mechanical impulse to the pipette tip received in the pipette tip receiving device where the pipette tip can move in this way is shaped or deformable that a metering amount in the nanoliter range can be metered by the transmission of the mechanical impulse from the trigger plunger to the deforming section of the pipetting tip.
  • the first and the second deformation formation can be moved relative to one another between a more distant one Loading position in which the pipette tip receiving device for receiving a pipette tip into the pipette tip receiving device and / or for removing a pipette tip from the pipette tip receiving device direction is configured, and a more closely approximated deformation position, in which a portion located in the deformation region of a pipette tip received in the receiving space is deformed by the first and second deformation deformations.
  • An undeformed conventional pipette tip which usually extends along a virtual tip axis between its coupling longitudinal end and its metering longitudinal end, does not allow metering of metering amounts in the nanoliter range due to transfer from outside due to undesirably high internal friction in relation to the metered quantity of large metering liquid quantities in its reservoir space mechanical impulses.
  • Such a liquid metering is rather made possible by liquid spaces which have a small clear width of at least 1 mm or less in at least one spatial direction orthogonal to the tip axis, so that a mechanically induced pressure wave in such a narrow metering liquid area spreads along the tip axis of the pipetting tip can and when the meniscus near the metering opening is reached, throws off a drop from the metering liquid supply provided.
  • the clear width between the first and the second deformation formation is preferably smaller in the deformation position in at least one spatial direction orthogonal to the receiving axis in the deformation area than in the receiving area of the receiving space located axially with respect to the virtual receiving axis on both sides of the deformation area.
  • the deformation area can be distinguished from the other receiving areas and can be recognized as a deformation area.
  • the deformation region thus forms a constriction of the receiving space in the at least one spatial direction orthogonal to the receiving axis.
  • the control device is preferably designed to drive the trigger plunger for displacement from the ready position into the trigger position only when the first and the second deformation deformation are in the deformation position.
  • the deformation area in the receiving space is changed in such a way that a section of a pipetting tip accommodated therein has a shape which allows metering of a metering liquid in the nanoliter range by external transmission of a mechanical impulse by means of the trigger plunger.
  • the change in shape caused by the two deformation formations in the receiving space is therefore a deformation of a pipetting tip that prepares a dosage.
  • the liquid metering device is preferably designed to deform a portion of a pipette tip accommodated in the receiving space in the deformation region over a deformation period which is long compared to the displacement period which the displacement movement of the trigger plunger takes from the standby position to the trigger position.
  • the deformation duration defined by the arrangement of the first and the second deformation formation in the deformation position lasts for at least several seconds , preferably for at least one minute, while the displacement of the trigger plunger from the ready position to the trigger position takes less than 1 second, preferably less than 0.25 seconds and particularly preferably less than 0.05 seconds.
  • the deformation duration is therefore at least preferred three times, particularly preferably at least thirty times as long as the relocation time.
  • the trigger plunger is preferably not only shifted from the ready position to the trigger position, but is immediately moved back from the trigger position back to the ready position, so that the trigger plunger does not remain in the trigger position, but rather the trigger position merely a reversal dead center of the trigger shift Release plunger is.
  • the control device and / or the displacement drive can be designed to hold the trigger plunger in the trigger position for a predetermined or a predeterminable period of time before its return to the ready position begins.
  • the liquid metering device can have an input / output device in order to transmit data to it or to input it manually or to have it retrieved by it, for example the above-mentioned holding period of the trigger plunger in the trigger position or one or more operating parameters of the metering.
  • the release plunger can be provided separately from the first and second deformation deformation, which in particular facilitates the formation of the release plunger with low mass and, as a result, its acceleration to high displacement speeds in a short time.
  • the trigger plunger in the deformation region of the receiving space defined by the first and the second deformation formation is to transmit force, it is preferred if the trigger plunger is at least part of the first deformation formation, since this is already arranged on the deformation region.
  • the trigger plunger is preferably the first deformation formation to reduce the number of components required to form the liquid metering device.
  • the trigger plunger can initially be used to deform the contribute to the pipetting tip and, when the first and the second deformation formation are in the deformation position, are abruptly shifted relative to the second deformation formation into the trigger position.
  • the position of the trigger plunger, which it assumes in the deformation position relative to the second deformation formation is then preferably the ready position.
  • the trigger plunger can be movable in a first deformation movement for deforming a pipetting tip received in the receiving space, so that the pipetting tip is deformed into its ready position by moving the trigger plunger from a starting position which is further retracted from the receiving space. After the ready position has been reached, the trigger plunger can then be abruptly displaced into the trigger position for the ballistic delivery of a metered quantity. Preferably, however, the trigger plunger can only be shifted between the ready position and the trigger position.
  • the second deformation formation which is preferably opposite the trigger plunger in a direction orthogonal to the receiving axis, comprises a wall section delimiting the receiving space.
  • An outer wall section of a pipetting tip can then be placed against this wall section, for example in a nesting manner, when the first and the second deformation formation are moved relative to one another from the loading position into the deformation position.
  • the pipette tip receiving device can have a first device part closer to the trigger plunger and a second device part further away from the trigger plunger.
  • the first or the second device part can, in addition to the trigger plunger, cause a pipette tip received in the receiving space to deform, for example to locally increase a flow resistance of the pipette tip along the tip axis.
  • the first and / or the second device tion part with respect to the receiving axis axial distance from the trigger plunger have a constriction section, in which the receiving space, at least in the deformation position, has a smaller cross-sectional area than axially un indirectly on both sides of the constriction section.
  • the above-mentioned first deformation formation can thus include both the trigger plunger and the, preferably first, device part with the constriction section.
  • the first device part can be arranged in a fixed position relative to a device frame of the liquid dosing device, that is to say fixed to the frame.
  • a device frame of the liquid dosing device that is to say fixed to the frame.
  • the trigger plunger is preferably also fixed to the frame in its ready position. The deformation movement is then carried out only by the second part of the device and the triggering displacement only by the trigger plunger.
  • a spatially compact pipette tip receiving device with the smallest possible space requirement can be obtained in that the first part of the device is penetrated or enforceable by the trigger plunger.
  • the second deformation formation can advantageously be formed on the second device part.
  • the two deformation formations can be moved manually between their loading position and their deformation position, the liquid metering device preferably having a guide formation which leads the two device formations relative to one another to their movement between the loading position and the deformation position.
  • the liquid metering device can have a movement drive which drives the two deformation formations relative to one another to their movement in at least one direction between the loading position and the deformation position, preferably in both directions.
  • the second deformation formation is preferably coupled to the motion drive alone.
  • the liquid metering device preferably has a motion drive coupled to the second device part, through which the second device part between an opening position further away from the first device part and one to the first device part closer closed position is movable.
  • the first and the second deformation formation are preferably in the loading position relative to one another when the second device part is in the open position, and then when the second device part is in the closed position , in the deformed position.
  • the second device part In order to prevent the movement drive from being energized or generally supplied with energy for the entire duration of the deformation of a pipette tip in the deformation region of the receiving space, provision can be made for the second device part to be biased into one of its positions.
  • the second device part is biased into the closed position, so that a biasing device providing the bias, such as a mechanical and / or pneumatic or / and hydraulic spring arrangement, also provides the deformation force by which a pipette tip received in the receiving space is deformed in sections. Then the movement drive only needs to be provided with energy for a short time in order to move the second device part into the open position or the first and the second deformation formation relative to one another into the loading position.
  • the trigger plunger can be preloaded in one of its positions by a preloading device, for example in turn by a mechanical or / and pneumatic or / and hydraulic spring arrangement.
  • the trigger plunger is preferably preloaded into the ready position, so that it only needs to be shifted into the release position abruptly against the preloading force of the preloading device by the displacement drive and after reaching the release position immediately by switching off the relocation drive to the standby position.
  • a particularly short displacement period and, in particular, a particularly short dwell time of the trigger plunger in the trigger position can be achieved.
  • the trigger position of the trigger plunger can be defined by a mechanical stop for the most precise possible pulse transmission from the trigger plunger to a deformation section of a pipetting tip accommodated in the receiving space.
  • the stop for adjusting the liquid metering device to different metering liquids and / or to different metering quantities along the displacement path of the trigger plunger is adjustable.
  • the displacement path of the trigger plunger can thus also be changeable.
  • a particularly effective pulse transfer from the trigger plunger to a deformation section of a pipetting tip can be achieved if a displacement path along which the trigger plunger can be displaced between its ready position and its triggering position has a virtual angle in the range from 70 ° to 110 ° with the virtual receiving axis includes.
  • the included angle is preferably a right angle, so that the trigger plunger can strike the deformation section of a pipetting tip as orthogonally as possible with the tip axis which is at least parallel or even collinear with the receiving axis.
  • a movement path, along which the first and second device parts are approachable to one another includes an angle in the range of 70 ° to with the virtual receiving axis 110 ° on.
  • the angle is preferably a right angle to advantageously avoid deformation components acting along the receiving or tip axis.
  • the displacement path and the movement path lie at least in sections, preferably completely, in two mutually parallel planes or on a common level.
  • the liquid metering device comprises a pipette tip.
  • a pipetting tip has a coupling longitudinal end, which has a coupling formation which is designed for coupling to a pipetting channel of a pipetting device, and has a metering longitudinal end opposite the coupling longitudinal end, which has a metering opening through which the discrete metered quantity can be dispensed.
  • the pipette tip further has a reservoir space between the coupling longitudinal end and the longitudinal dosing end, in which the dosing liquid supply can be received.
  • the pipette tip extends between its coupling end and its dosing end along a virtual tip axis.
  • the pipette tip projects axially relative to the deformation area with respect to the tip axis, preferably on both sides.
  • a deformed section of the pipetting tip that is actually deformed by the first and the second deformation formation is adjoined on both sides by undeformed pipetting tip sections.
  • These are preferably at least in sections rotationally symmetrical with the tip axis as a rotational symmetry axis.
  • the reservoir space preferably projects axially beyond the deformation region on both sides.
  • the pressure wave induced by the trigger plunger in the dosing liquid of the deformed pipette tip spreads from the point of impact of the trigger plunger to a deformation section of the pipette tip arranged in the deformation region of the receiving space.
  • the pressure wave is damped along the propagation path by internal friction in the dosing liquid.
  • the deformation region is closer to the dosing end than to the coupling end. Then the pressure wave reaches the meniscus of the metering liquid closer to the metering opening as undamped as possible.
  • the deformation region is preferably located completely in the half of the axial extension region of the pipetting tip that extends from the longitudinal end of the dosing.
  • the pipette tip in its state accommodated in the receiving space, with the first and the second deformation formation being in the deformation position, has a deformation section located in the deformation region of the receiving space with two inner wall surface sections opposite one another via a gap in the interior of the pipetting tip.
  • the gap produced by the deformation formations on the pipette tip has a gap width of at least 20 mm, preferably of at least 50 pm and particularly preferably of at least 70 pm in the direction orthogonal to the tip axis.
  • the gap width is not larger than 900 pm, preferably not larger than 500 pm and particularly preferably not larger than 200 pm. In tests, a gap width of 100 pm has proven to be particularly advantageous.
  • the trigger plunger contacts the deformation section of the pipette tip in the release position.
  • the release plunger can contact the deformation section before reaching the release position, so that the release plunger deforms for a short time from contacting the deformation section until reaching the release position.
  • This trigger deformation which extends over a considerably shorter period of time than the deformation of the deformation section by the deformation formations, is added to the latter, a dosage-preparing deformation for a short time, for example for a period in the two-digit or low three-digit millisecond range.
  • the release deformation is preferably an exclusively elastic deformation.
  • the deformation preparing the dosage has a plastic deformation component because of its higher degree of deformation compared to the release deformation and the longer deformation duration.
  • the object mentioned at the outset is also achieved by a pipetting device with a pipetting channel which extends along a virtual channel path and which is at least partially filled with a working fluid which is different from the metering liquid and which has a coupling formation at its free longitudinal end for temporary use , Detachable coupling of a pipetting tip thereon, the pipetting device further comprising: a pressure change device which is designed to change the pressure of the working fluid in the pipetting channel,
  • a pressure sensor which is designed and arranged to detect the pressure of the working fluid in the pipetting channel
  • a pipetting control device which is connected to control the operation of the pressure change device for signal transmission with both the pressure sensor and the pressure change device, and which is designed to control the operation of the pressure change device at least in accordance with an actual working fluid pressure detected by the pressure sensor, and
  • the pipetting device comprises a liquid metering device configured according to the above description, the pipetting tip with its coupling formation being coupled or connectable to the coupling design of the pipetting channel, and furthermore the pipetting control device is designed to operate the pressure changing device at least in accordance with the actual value detected by the pressure sensor.
  • Working fluid pressure preferably taking into account at least one predetermined target working fluid pressure value.
  • the pipetting control device is controlled by a corresponding control of the pressure changing device by mechanical impulse transfer from the deformation section of the dosing liquid from a dosing liquid supply located axially between the coupling formation and the deformation section can lead into the deformation section.
  • the above object is also achieved by a pipetting tip for use in a device as described above. wrote configured liquid metering device which extends along a virtual tip axis, the pipetting tip having:
  • a dosing longitudinal end axially distant from the coupling longitudinal end, with respect to the tip axis, with a dosing opening through which a discrete dosing quantity can be dispensed from a dosing liquid supply received in the pipetting tip,
  • a section of the pipette tip located between the metering opening and the coupling formation has, as the deformation section, two inner wall surface sections opposite one another via a gap in the interior of the pipette tip, the gap being at least five times in a first larger direction of extension orthogonal to the tip axis parallel to the opposite inner wall surface sections, preferably has at least ten times, particularly preferably at least 50 times as large a clear width as in a second smaller extension direction orthogonal both to the tip axis and to the first direction of extension.
  • Such a pipette tip is designed for use in the described liquid metering device, regardless of whether the deformation section is already formed on the pipette tip before being accommodated in the receiving space of the pipette tip receptacle or whether it is only deformed by means of the first and the second deformation forma tion is generated.
  • the dimension of the gap along the tip axis is at least 0.5 times its size maximum clear width along the first direction of extent.
  • the dimension of the gap along the tip axis should not be more than 0.8 times, preferably not more than 0.5 times, particularly preferably not more than a third of the axial length of the pipette tip.
  • the coupling formation can be located far enough from the deformation section in order not to be undesirably deformed.
  • the pipette tip preferably has a rotationally symmetrical body section on at least one axial (with respect to the tip axis) side of the deformation section, preferably axially on both sides of the deformation section.
  • the deformation section in order to have a sufficient size for the mechanical pulse transmission and the resulting introduction of a pressure wave into the dosing liquid in the deformation section, along the first direction of extension at least one, with respect to the tip axis, axially adjoining body portion of the pipetting tip radially tower over.
  • the deformation section preferably projects radially in each of two opposite radial directions from a body section axially adjoining the deformation section.
  • the gap formed in the deformation section is preferably thin, with a gap width of less than one millimeter. Therefore, a, with respect to the tip axis, axially adjoining the deformation section of the body portion of the pipette tip radially protrude beyond the deformation section along the second direction of extension. Preferably, each of two axially on both sides of the deformation section on these adjoining body sections projects radially beyond the deformation section along the second direction of extension.
  • the above-mentioned object is also achieved by a method for the ballistic delivery of a discrete one Dosing quantity of dosing liquid in a dosing volume range from 0.3 nl to 900 nl from a dosing liquid supply, comprising the following steps:
  • a pipette tip extending along a virtual tip axis with a coupling formation formed on a, with respect to the tip axis, axial longitudinal end for coupling to a pipetting animal device, with a metering opening formed at an axial distance from the coupling formation for dispensing the metered quantity, and with an intermediate the coupling formation and the metering opening located reservoir space for receiving the metering liquid supply,
  • the step of exerting the impulse-like impulse transmission has a further deformation of the deformation section beyond the dosage-preparatory deformation of the reservoir space section to form the deformation section through the first and the second deformation formation, the duration of the further deformation of the deformation section being preferably not more than a third wise is not more than a tenth of the duration of the dosage-preparatory deformation to form the deformation section.
  • dosing quantities of 0.3 nl to 5 nl can be dosed repeatedly. With somewhat larger dimensions, such as the gap size in the deformation section of the pipette tip, dosing quantities in the range from 5 nl to 20 nl can be dosed repeatedly.
  • a next more robust embodiment of the liquid dosing device can dispense dosing quantities in the range from 20 nl to 70 nl exactly. It is also possible with a liquid dosing device to dispense dosing quantities in the range from 70 nl to 500 nl exactly as single drops. The delivery of quantities in the range from 500 nl to 900 nl is also exactly possible, but here the risk increases that a drop of fluff forms in the metered amount of liquid and separate satellite drops form from this, which is not always acceptable.
  • FIG. 1 is a side view of an embodiment of a liquid metering device according to the invention with a pipette tip, a first and a second part of the device of the liquid metering device being shown in an exploded view of a fluff body of the device, and the pipette tip being coupled to a pipetting channel of a pipetting device,
  • Fig. 2 is a perspective view of the embodiment of Fig. 1 without
  • FIGS. 1 to 3 shows the first and second device parts used in FIGS. 1 to 3 in a perspective view of their surfaces to be pointed towards one another during operation
  • 5A is a view of a conventional undeformed pipette tip
  • FIG. 5B is a side view of the pipette tip of FIG. 5A in a state deformed by the first and the second deformation formation
  • Fig. 5C the pipette tip of Fig. 5A in a deformed shape in a front view of the deformation section.
  • an embodiment of a liquid metering device according to the invention is generally designated 10.
  • the liquid metering device 10 comprises a housing 12 which is generally stationary during operation, for example fixed to the frame, on which a pipette tip receiving device 14 is provided.
  • the pipette tip receiving device 14 comprises, for example, a first device part 16 which is generally fixed to the housing or frame and a second device part 18 which is movable relative to the first.
  • the liquid metering device 20 has two manually operable screws 24a and 24b.
  • the screws 24a and 24b can be used to bring the second device part 18 closer to the first device part 16 into the closed position with a defined force.
  • the movement drive 24 can have an actuating actuator which can be coupled along the movement path B for the joint movement with the second device part 18.
  • the movement drive 24 can be a pneumatically or hydraulically actuated movement drive, the piston rod or piston rods of which can be coupled to the second device part 18 for joint movement.
  • the movement drive 24 can be an electromotive movement drive, for example a spindle drive, to take up the functional principle of the screws 24a and 24b shown as examples.
  • a threaded rod of the spindle drive can be screw-engaged with an internal thread of an opening passing through the second device part 18 parallel to the movement path B, so that the second device part 18 acts as a nut which, when the at least one threaded rod rotates along the thread, along the longitudinal axis of the rod corresponding to the speed and the pitch of the thread used on the threaded rod is moved along the movement path B.
  • the first device part 16 can also be driven by a movement drive for movement along the movement path B, but this would only increase the number of movement drives to be provided without the associated benefit being appreciably increased.
  • the second device part 18 could be housing or set test and only the first device part 16 could be displaceable along the movement path B by a movement drive.
  • the first and second Vorrich device part 16 and 18 will be discussed in more detail below in connection with FIG. 4. First, however, the functionality of the liquid metering device 10 is to be explained further.
  • the liquid metering device 10 has a trigger plunger 26 which can be displaced along a displacement path V between a standby position drawn further back into the housing 12 and a trigger position pushed further out of the housing 12.
  • the displacement path V and the movement path B are preferably collinear or at least parallel.
  • the flub of the trigger plunger 26 between its two operating positions mentioned is considerably smaller than the relative movement path of the first device part 16 and the second device part 18 along the movement path B between their operating positions: open position and closed position. While the relative movement path of the first and second device parts 16 and 18 is at least in the single-digit millimeter range, the stroke of the trigger plunger 26 between its stated operating positions: ready position and trigger position, usually less than 50 miti, preferably less than 40 miti , particularly preferably less than 36 miti.
  • the information on the stroke of the trigger plunger and on the relative movement of the first and second Vorrich device part 16 and 18 apply not only to the exemplary embodiment shown in FIGS. 1 to 3 of the present invention, but in general for the liquid metering device present invention.
  • the stroke of the trigger plunger is preferably always smaller, approximately at least a factor of 5 smaller than the path of movement of the device parts 16 and 18 between their operating positions.
  • the liquid metering device 10 has a better clarity because of the control device 28 shown only in FIGS. 1 and 3 in dashed lines in the housing 12.
  • the Steuerervor device 28 is connected to a displacement drive 30 in the exemplary form of a piezo actuator through line 32 in signal transmission connection.
  • a displacement drive 30 in the exemplary form of a piezo actuator through line 32 in signal transmission connection.
  • connection sockets 34a and 34b energy, in the example shown electrical energy through the connection socket 34a, and data, in the example shown through the connection socket 34b in the form of an RJ45 socket, can be transmitted into the interior of the housing 12.
  • the energy can be supplied as drive energy by the control device 28 via the line 32 to the piezo actuator of the displacement drive 30.
  • the housing 12 can be spatially aligned with respect to a frame and / or with respect to the pipetting device 60 shown in FIG. 1.
  • the displacement drive 30 can comprise an electromagnet, which generates or does not generate a magnetic field by energizing or not energizing, which displaces the trigger plunger 26.
  • the trigger plunger 26 can comprise a permanent magnet or a soft magnetic armature, which can be displaced along the displacement path V together with the trigger plunger 26 carrying it, due to the magnetic field generated by the electromagnetic displacement drive depending on its energization state.
  • the trigger plunger 26 protrudes into a recess 38 which penetrates the first device part 16 and penetrates it both in its ready position and in its trigger position.
  • first device part 16 and second device part 18 are explained in more detail:
  • the mutually facing surfaces 16a and 18a of the two device parts 16 and 18 have a contour such that when the two device parts 16 and 18 along the movement path B are in their approximate closed position between the two device parts 16 and 18 18 a receiving space 40 is defined, in which at least one axial section of a pipette animal tip 42 can be accommodated.
  • the receiving space 40 extends along a virtual receiving axis A, which coincides with a virtual tip axis S of a pipetting tip 42 received in the receiving space 40.
  • the Vorrich device parts 16 and 18 are in their closed position.
  • the trigger plunger 26, the first device part 16 penetrated by it and the second device part 18 have deformation formations which define a deformation area 44 on the pipette tip receiving device 14, in which a conventional pipette tip 42 accommodated in the receiving space 40 is mechanically deformed in sections. when the first and second parts 16 and 18 are in the closed position.
  • the deformation deformations mentioned comprise a first deformation formation 46 closer to the housing 12 and a second deformation formation 48 realized on the second device part 18.
  • the first deformation formation 46 comprises the end face 46a of the trigger plunger 26 pointing towards the second device part 18 (see FIG. 1) and comprises a constriction section 46b provided along the receiving axis A at a distance from the through opening 38 on the first device part 16.
  • the second deformation formation 48 comprises an essentially flat surface 48a on the second device part 18 and orthogonal to the movement path B. a step section 48b, with which a clear width between the surfaces 16a and 18a of the device parts 16 and 18 to be pointed towards one another is gradually tapered in the deformation region 44.
  • the step region 48b can alternatively also be formed entirely or partially by an inclined surface.
  • the deformation formation 46 is formed on the release plunger 26 and on the first device part 16, since the deformation formation 48 is formed on the second device part 18 and finally the release plunger 26 remains in its standby position at least until the first and the second device part 16 or 18 are in their closed position, the deformation formations 46 and 48 are then in a deformed position deforming a pipette tip 42 when the first and second device parts 16 and 18 are in the closed position and the trigger plunger 26 is in the ready position . Further, the deformation formations 46 and 48 are then in a loading position which facilitates the taking up or removal of a pipette tip 42 from the pipette tip receiving device 14 when the first and second device parts 16 and 18 are in the open position.
  • the position of the release tappet 26 is not important. However, this will be in the standby position, since the control device 28 is designed to only move the trigger plunger 26 into the trigger position when the device parts 16 and 18 are in the closed position.
  • the release plunger 26 protrudes more strongly into the receiving space 40, in particular in its deformation region 44, than in its standby position.
  • the end face 46a of the trigger plunger 26 and the face 48a of the second device part 18 face each other and define a substantially flat gap with a constant gap dimension to be measured along the movement path B over the entire area through the end face 46a of the illustrated example Trigger plunger 26 defined gap area.
  • the end face 46a of the trigger plunger 26 or / and the face 48a of the second deformation formation 48 can have a contour that deviates from a flat shape. Manufacturing technically simpler, however, is the generation of flat surfaces to share the construction mentioned.
  • the constriction section 46b is intended to constrict a pipetting tip 42 received in the receiving space 40 on the side of the through-opening 38 which is further away from a metering opening 50 of the pipetting tip 42. With this constriction, the clear width inside the pipette tip 42 is to be reduced and thereby the flow resistance of metering liquid in the pipette tip 42 is to be increased, starting from the deformation region 44 in the direction away from the metering opening 50.
  • the aim of this is to ensure that when the trigger plunger 26 mechanically exerts a short mechanical pulse with a duration in the two-digit or low three-digit millisecond range on a deformed section of the pipette tip 42 in the deformation region 44 of the pipette tip receiving device 14, one of them Pressure wave induced in the dosing liquid of the pipetting tip 42 leads to a dosing drop being thrown off through the dosing opening 50 and not, for example, to a liquid movement away from the dosing opening 50 towards larger cross sections of the pipetting tip 42 tapering conically towards the dosing opening 50.
  • conventional pipetting tips 42 can advantageously be used for metering metering liquid in metered quantities in the nanometer range, although the conventional pipetting tips 42 in the undeformed initial state are only designed for metering metering liquids in the so-called “air displacement” method are, with no dosing amounts in the nanoliter range being dosed in the dosing method mentioned.
  • a conventional pipette tip 42 in its undeformed state before receiving a portion of the same in the receiving space 40 of the pipette tip receiving device 14 and before moving the device parts 16 and 18 into the closed position is shown in FIGS. 1, 2 and 5A.
  • Such a conventional pipette tip 42 has at its metering longitudinal end 52 the metering opening 50 and at its opposite coupling longitudinal end 54 has a coupling formation 56 for coupling to a pipetting channel 58 shown in FIG. 1 of a pipetting device 60.
  • the pipetting tip 42 which extends along the virtual tip axis S intended to penetrate it centrally, has a reservoir space 62 between the coupling longitudinal end 54 and the longitudinal dosing end 52, in which a dosing liquid supply can be received, for example by aspiration through the dosing opening 50.
  • constriction section 46b in the first device part 16 forms in the closed position of the device parts 16 and 18 a constriction in the reser voirraum 62 on the section protruding from the gap formed between the release plunger 26 and the surface 48a in the direction of the coupling end 54 Pipette tip 42.
  • the deformation area 44 of the pipetting tip receiving device 14 and the trigger plunger 26 is formed as a deformation section 64 on the pipetting tip 42.
  • the pipetting tip 42 is preferably designed to be rotationally symmetrical with respect to its tip axis S as a rotational symmetry axis in the undeformed state.
  • FIG. 5C As can be seen from the slightly different deformation of the pipette tip 42 'in FIG. 5C compared to the pipette tip 42 of FIG. 5B, these figures show different pipette tips 42 and 42'. Identical and functionally identical sections of the pipette tip 42 'of FIG. 5C are therefore designated by the same reference symbols as on the pipette tip 42 of the other figures, but provided with an additional apostrophe.
  • the embodiment of FIG. 5C is described below only insofar as it differs from that of FIG. 5B, to the description of which reference is also otherwise made to explain embodiment 42 'of FIG. 5C.
  • the deformation section 64 has a substantially larger dimension in a first direction of extension E1 orthogonal to the tip axis S than in a second direction of extension E2 orthogonal to both the tip axis S and the first direction of extension E1.
  • the dimension of the deformation section 64 or 64 ′ in the first direction of extension E1 is preferably at least five times as large as the dimension in the second direction of extension E2.
  • the deformation section 64 or 64 ' projects radially with respect to the tip axis S the two directly undeformed body sections 66 and 68 or 66' and 68 'which are axially adjacent on both sides of the deformation section 64 or 64'.
  • the pipetting tip 42 or 42 'in the deformation section 64 or 64' is deformed radially to such an extent that the undeformed body sections 66 and 68 adjacent to the deformation section 64 or 64 'along the second extension direction E2 deform the deformation section 64 or 64 'protrude radially.
  • the second extension direction E2 runs parallel to the movement path B and thus also parallel to the displacement path V.
  • the first extension direction E1 runs both orthogonally to the second extension direction E2 and orthogonally to the tip axis S or to the receiving axis A.
  • the deformation section 64 has at least on its outer side two parallel flat surface sections 64a and 64b.
  • the gap space formed internally by the deformation section 64 or 64 ′ can likewise be formed by flat or / and mutually parallel inner surface sections. This is possible in particular when the wall thickness of the pipette animal tip 42 or 42 'is constant along its axial extent or at least along the reservoir space 62 or 62'.
  • the gap space formed in the interior of the pipetting tip 42 or 42 'in the deformation section 64 or 64' preferably has a clear width in the second direction of extension of approximately 100 pm. This value is only mentioned as an example. In contrast, in the first direction of extension E1, the gap can have a clear width of 5 mm or more.
  • the deformation space 64 or 64' is formed along the tip axis S with the largest dimension. This also applies to the formed by the deformation section 64 or 64 ' th gap. It can be formed along the tip axis S at least twice as long as along the first direction of extension E1.
  • the deformation section 64 or 64 'of the pipette tip 42 or 42' is the triggering section, in which the trigger plunger 26 transmits a brief mechanical shock-like impulse to the metering liquid received in the pipette tip 42 or 42 'in order to determine a metered quantity in If the nanoliter area is ballistically thrown through the metering opening 50 or 50 ', the deformation section 64 or 64' is preferably arranged closer to the metering opening 50 or 50 'than at the coupling formation 56 or 56'.
  • the deformation section 64 or 64 ' is preferably formed completely in the axial extension half of the pipette tip 42 extending from the metering opening 50.
  • the liquid metering device 10 is excellently suitable for aliquoting, in which, for example, the displacement drive 30 is operated by the control device 28.
  • the metering of metered liquid quantities in the nanoliter range can also be supported by the pipetting device 60 shown by way of example and roughly in FIG. 1.
  • the pipetting device 60 with its pipetting channel 58 can be coupled to the coupling formation 56 of the pipetting tip 42 via a coupling formation 70, which is only indicated in FIG. 1.
  • Gas is present as working fluid in the pipetting channel 58, the pressure of which can be detected by a pressure sensor 72.
  • the pressure of the working fluid in the pipetting channel 58 can be changed in a manner known per se by a pressure changing device 74, which can comprise, for example, a pipette animal piston 76 which can be displaced along a channel axis K in the pipetting channel 58.
  • the pressure changing device 74 can have an adjustment drive 78 beyond the pipetting piston 76, through which the pipetting piston 76 can be adjusted along the channel path K in the pipetting channel 58 and consequently the pressure of the working fluid in the pipetting channel 58 can be changed.
  • a pipetting control device 80 which is connected to both the pressure sensor 72 and the adjusting drive 78 of the pipetting piston 76 for signal transmission, can adjust the pipetting piston 76 as a function of an actual working fluid pressure measured by the pressure sensor 72 and possibly further as a function of one in one Storage device of the pipetting control device 80 cause the desired working fluid pressure to be deposited by appropriate actuation of the adjustment drive 78.
  • the pipetting control device 80 can be connected in terms of signal transmission to the control device 28 of the liquid metering device 10.

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  • Health & Medical Sciences (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Human Computer Interaction (AREA)
  • Devices For Use In Laboratory Experiments (AREA)
  • Feeding, Discharge, Calcimining, Fusing, And Gas-Generation Devices (AREA)
  • Sampling And Sample Adjustment (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Abstract

Dispositif de dosage de liquides (10) pour l'émission ballistique d'une quantité discrète de dosage d'un liquide de dosage dans une plage de volume de dosage comprise entre 0,3 nl et 900 nl à partir d'une réserve de liquide de dosage, comprenant : - une un dispositif de réception de pointe de pipette (14), lequel définit, dans une position de fonctionnement prête pour le dosage du dispositif de dosage de liquides (10), au moins un espace de réception (40) s'étendant le long d'un axe de réception (A) virtuel, lequel est conçu pour la réception d'une section d'une pointe de pipette (42), - un poussoir de déclenchement (26) mobile par rapport au dispositif de réception de pointe de pipette (14), lequel est déplaçable entre une position d'attente retirée de l'espace de réception (40) et une position de déclenchement engagée dans l'espace de réception (40), - un entraînement de déplacement (30) couplé en transmission de mouvement avec le poussoir de déclenchement (26), et - un dispositif de commande (28) pour la commande du fonctionnement de l'entraînement de déplacement (30). Selon l'invention, le dispositif de dosage de liquides (10) présente une première (46) et une deuxième formation de déformation (48), la première (46) et la deuxième formation de déformation (48) définissant entre elles une zone longitudinale de l'espace de réception (40) comme zone de déformation (44), dans laquelle la première (46) et la deuxième formation de déformation (48) peuvent être rapprochées et éloignées l'une de l'autre, le poussoir de déclenchement (26) se trouvant dans sa position de déclenchement dans la zone de déformation (44) de l'espace de réception (40).
EP19813503.0A 2018-12-05 2019-12-02 Dispositif de dosage de liquides pour l'émission ballistique de quantités de dosage dans la plage de nanolitres, procédé de dosage de liquides et pointe de pipette pour celui-ci Pending EP3890888A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102018131088.9A DE102018131088A1 (de) 2018-12-05 2018-12-05 Flüssigkeitsdosiervorrichtung zur ballistischen Abgabe von Dosiermengen im Nanoliterbereich, Flüssigkeitsdosierverfahren und Pipettierspitze hierfür
PCT/EP2019/083280 WO2020114954A2 (fr) 2018-12-05 2019-12-02 Dispositif de dosage de liquides pour l'émission ballistique de quantités de dosage dans la plage de nanolitres, procédé de dosage de liquides et pointe de pipette pour celui-ci

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EP3890888A2 true EP3890888A2 (fr) 2021-10-13

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US (1) US20220023852A1 (fr)
EP (1) EP3890888A2 (fr)
JP (1) JP7391964B2 (fr)
CN (1) CN113164962B (fr)
DE (1) DE102018131088A1 (fr)
WO (1) WO2020114954A2 (fr)

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JP2022511042A (ja) 2022-01-28
CN113164962B (zh) 2023-06-27
JP7391964B2 (ja) 2023-12-05
WO2020114954A3 (fr) 2020-07-30
CN113164962A (zh) 2021-07-23
US20220023852A1 (en) 2022-01-27
WO2020114954A2 (fr) 2020-06-11
DE102018131088A1 (de) 2020-06-10

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